CH666272A5 - CARBAPENEM DERIVATIVES. - Google Patents
CARBAPENEM DERIVATIVES. Download PDFInfo
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- CH666272A5 CH666272A5 CH2956/86A CH295686A CH666272A5 CH 666272 A5 CH666272 A5 CH 666272A5 CH 2956/86 A CH2956/86 A CH 2956/86A CH 295686 A CH295686 A CH 295686A CH 666272 A5 CH666272 A5 CH 666272A5
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- C—CHEMISTRY; METALLURGY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
- C07D213/20—Quaternary compounds thereof
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
L'invention concerne de nouveaux composés de formule: The invention relates to new compounds of formula:
,8 h , 8 a.m.
-a-i cook -a-i cook
(II) (II)
3 3
666272 666272
dans laquelle R1, R2', R8 et A ont les définitions données dans la revendication 1. Les composés de la présente invention sont utiles comme intermédiaires à la préparation des nouveaux dérivés de car-bapenem décrits et revendiqués dans le brevet de base et des compositions pharmaceutiques qui contiennent les dérivés de carbapenem biologiquement actifs conjointement avec des supports ou des diluants pharmaceutiquement acceptables. in which R1, R2 ', R8 and A have the definitions given in claim 1. The compounds of the present invention are useful as intermediates in the preparation of the new car-bapenem derivatives described and claimed in the basic patent and of the compositions pharmaceuticals which contain the biologically active carbapenem derivatives together with pharmaceutically acceptable carriers or diluents.
Les nouveaux composés de formule générale II ci-dessus contiennent le noyau carbapenem: The new compounds of general formula II above contain the carbapenem nucleus:
1 1
et ils peuvent, par conséquent, être qualifiés de dérivés d'acide 1-car-ba-2-penem-3-carboxylique. A titre de variante, les composés peuvent être considérés comme ayant la structure de base: and they can therefore be qualified as 1-car-ba-2-penem-3-carboxylic acid derivatives. As a variant, the compounds can be considered to have the basic structure:
et on peut les appeler dérivés d'acide 7-oxo-l-azabicylo(3.2.0)hept-2-ène-2-carboxylique. Bien que la présente invention couvre les composés dans lesquels la stéréochimie relative des protons en positions 5, 6 correspond à la configuration eis de même qu'à la configuration trans, les composés préconisés ont la stéréochimie 5R, 6S (trans) comme dans le cas de la thiénamycine. and they can be called 7-oxo-1-azabicylo (3.2.0) hept-2-ene-2-carboxylic acid derivatives. Although the present invention covers the compounds in which the relative stereochemistry of the protons in positions 5, 6 corresponds to the eis configuration as well as to the trans configuration, the recommended compounds have the 5R, 6S (trans) stereochemistry as in the case thienamycin.
Les composés de formule I peuvent ne pas être substitués en position 6 ou bien ils peuvent être substitués par des groupes substituants déjà mentionnés à propos d'autres dérivés de carbapenem. R8 est l'hydrogène et R1 est l'hydrogène ou un radical substitué ou non, comme défini dans la revendication 1 (cf. la demande de brevet européen N° 38869, la définition de R6). A titre de variante, R8 et R1, The compounds of formula I may not be substituted in position 6 or they may be substituted by substituent groups already mentioned in connection with other carbapenem derivatives. R8 is hydrogen and R1 is hydrogen or a substituted or unsubstituted radical, as defined in claim 1 (cf. European patent application No. 38869, the definition of R6). As a variant, R8 and R1,
pris conjointement, peuvent former un groupe alkylidène en C2 à C10 ou alkylidène en C2 à C10 substitué par exemple par un radical hydroxy. taken together, can form a C2 to C10 alkylidene or C2 to C10 alkylidene group, for example substituted by a hydroxy radical.
On donne ci-après de plus amples détails sur les définitions de R1 et de R8 : Further details on the definitions of R1 and R8 are given below:
a) Les groupes aliphatiques «alkyle», «alcényle» et «alcynyle» peuvent être des groupes à chaîne droite ou à chaîne ramifiée ayant 1 àlO atomes de carbone; il s'agit avantageusement de groupes ayant 1 à 6 et notamment 1 à 4 atomes de carbone; lorsqu'il fait partie d'un autre substituant, par exemple dans cycloalkylalkyle ou hétéroaralkyle ou aralcényle, le groupe alkyle, alcényle ou alcynyle renferme avantageusement 1 à 6 et notamment 1 à 4 atomes dé carbone. a) The “alkyl”, “alkenyl” and “alkynyl” aliphatic groups may be straight chain or branched chain groups having 1 to 10 carbon atoms; they are advantageously groups having 1 to 6 and in particular 1 to 4 carbon atoms; when it is part of another substituent, for example in cycloalkylalkyl or heteroaralkyl or aralkenyl, the alkyl, alkenyl or alkynyl group advantageously contains 1 to 6 and in particular 1 to 4 carbon atoms.
b) Le terme «hétéroaryle» s'adressfe à des groupes hétérocycliques aromatiques mono-, bi- et polycycliques contenant 1 à 4 atomes d'oxygène, d'azote ou de soufre; on apprécie des noyaux hétérocycliques pentagonaux ou hexagonaux tels que thiényle, furyle, thia-diazolyle, oxadiazolyle, triazolyle, isothiazolyle, thiazolyle, imidazo-lyle, isoxazolyle, tétrazolyle, oxazolyle, pyridyle, pyrazinyle, pyrimi-dinyle, pyridazinyle, pyrrolyle, pyrazolyle, etc. b) The term "heteroaryl" refers to heterocyclic aromatic mono-, bi- and polycyclic groups containing 1 to 4 atoms of oxygen, nitrogen or sulfur; pentagonal or hexagonal heterocyclic rings are appreciated such as thienyl, furyl, thia-diazolyl, oxadiazolyl, triazolyl, isothiazolyl, thiazolyl, imidazo-lyle, isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyridinyl pyyrinylpyrinylpyrinylpyrinylpyrinylpyridinylpyridinyl etc.
c) Le terme «hétérocyclyle» désigne des groupes hétérocycliques non aromatiques saturés ou insaturés monocycliques, bicycliques et polycycliques contenant 1 à 4 atomes d'oxygène, d'azote ou de soufre; on apprécie des noyaux hétérocycliques pentagonaux ou hexagonaux tels que morpholinyle, pipérazinyle, pipéridyle, pyrazol-inyle, pyrazolidinyle, imidazolinyle, imidazolidinyle, pyrrolinyle, pyrrolidinyle, etc. (c) The term "heterocyclyl" denotes saturated or unsaturated monocyclic, bicyclic and polycyclic non-aromatic heterocyclic groups containing 1 to 4 oxygen, nitrogen or sulfur atoms; pentagonal or hexagonal heterocyclic rings are appreciated such as morpholinyl, piperazinyl, piperidyl, pyrazol-inyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, etc.
d) «Halogéno» désigne les radicaux chloro, bromo, fluoro et iodo, et notamment le radical chloro ou bromo. d) “Halo” denotes the chloro, bromo, fluoro and iodo radicals, and in particular the chloro or bromo radical.
L'expression «groupe protégeant la Fonction carboxyle» désigne un groupe ester connu qui a été utilisé pour protéger un groupe carboxyle pendant les étapes réactionnelles chimiques décrites ci- The expression “group protecting the carboxyl function” designates a known ester group which has been used to protect a carboxyl group during the chemical reaction stages described above.
dessous et qui peut être éliminé éventuellement par des procédés qui n'entraînent aucune destruction notable de la portion restante de la molécule, par exemple par hydrolyse chimique ou enzymatique, par traitement avec des réducteurs chimiques dans les conditions douces, par irradiation avec la lumière ultraviolette ou par hydrogénation catalytique. Des exemples de ces groupes ester protecteurs comprennent les groupes benzhydryle, p-nitrobenzyle, 2-naphtylméthyle, allyle, benzyle, trichloréthyle, silyle tel que triméthylsilyle, phén-acyle, p-méthoxybenzyle, acétonyle, o-nitrobenzyle 4-pyridylméthyle et alkyle en Q à C6 tel que méthyle, éthyle ou tertiobutyle. Parmi ces groupes protecteurs, on compte ceux qui sont hydrolysés dans des conditions physiologiques telles que des groupes pivaloyloxy-méthyle, acétoxyméthyle, phtalidyle, indanyle et méthoxyméthyle. Des groupes particulièrement avantageux pour protéger la fonction carboxyle sont le groupe p-nitrobenzyle, qui peut être aisément éliminé par hydrogénolyse catalytique, et le groupe allyle, qui peut être éliminé par réaction catalysée par Pd(P03)4. underneath and which can possibly be eliminated by methods which do not cause any notable destruction of the remaining portion of the molecule, for example by chemical or enzymatic hydrolysis, by treatment with chemical reducers under mild conditions, by irradiation with ultraviolet light or by catalytic hydrogenation. Examples of these protective ester groups include benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl, trichlorethyl, silyl such as trimethylsilyl, phen-acyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl 4-pyridylmethyl and alkyl en Q to C6 such as methyl, ethyl or tert-butyl. Among these protective groups are those which are hydrolyzed under physiological conditions such as pivaloyloxy-methyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl groups. Particularly advantageous groups for protecting the carboxyl function are the p-nitrobenzyl group, which can be easily eliminated by catalytic hydrogenolysis, and the allyl group, which can be eliminated by reaction catalyzed by Pd (P03) 4.
Les dérivés de carbapenem pour lesquels les composés de formule II sont utiles comme intermédiaires ont la formule suivante: The carbapenem derivatives for which the compounds of formula II are useful as intermediates have the following formula:
s — s -
O O
dans laquelle R8 est l'hydrogène et R1 est choisi dans le groupe comprenant l'hydrogène; des radicaux substitués et non substitués tels qu'alkyle, alcényle et alcynyle ayant 1 à 10 atomes de carbone; cycloalkyle et cycloalkylalkyle ayant 3 à 6 atomes de carbone dans le noyau cycloalkyle et 1 à 6 atomes de carbone dans les portions alkyliques; phényle; aralkyle, aralcényle et aralcynyle dont la portion aryle est un groupe phényle et la portion aliphatique comprend 1 à 6 atomes de carbone; hétéroaryle, hétéroaralkyle, hétérocyclyle et hétérocyclylalkyle dont l'hétéroatome ou les hétéroatomes des portions hétérocycliques mentionnées ci-dessus sont choisis dans le groupe comprenant 1 à 4 atomes d'oxygène, d'azote ou de soufre, et les portions alkyle liées auxdites portions hétérocycliques ont 1 à 6 atomes de carbone; le substituant ou les substituants relatifs aux radicaux mentionnés ci-dessus sont choisis dans le groupe comprenant les radicaux suivants: alkyle en Ci à C6 éventuellement substitué par un radical amino, halogéno, hydroxy ou carboxyle: wherein R8 is hydrogen and R1 is selected from the group consisting of hydrogen; substituted and unsubstituted radicals such as alkyl, alkenyl and alkynyl having 1 to 10 carbon atoms; cycloalkyl and cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl portions; phenyl; aralkyl, aralkenyl and aralkynyl in which the aryl portion is a phenyl group and the aliphatic portion comprises 1 to 6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl in which the heteroatom or heteroatoms of the heterocyclic portions mentioned above are chosen from the group comprising 1 to 4 oxygen, nitrogen or sulfur atoms, and the alkyl portions linked to said heterocyclic portions have 1 to 6 carbon atoms; the substituent or the substituents relative to the radicals mentioned above are chosen from the group comprising the following radicals: C1-C6 alkyl optionally substituted by an amino, halogeno, hydroxy or carboxyl radical:
halogéno halo
-OR3 -OR3
O O
II II
—OCNR3R4 —OCNR3R4
O O
II II
— CNR3R4 - CNR3R4
—NR3R4 —NR3R4
NR3 NR3
NR3R4 NR3R4
-S02NR3R4 -S02NR3R4
O O
II II
—NHCNR3R4 —NHCNR3R4
O O
II II
R3CNR4— R3CNR4—
—C02R3 —C02R3
=o = o
O O
II II
-OCR3 -OCR3
5 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
666 272 666,272
4 4
-SR3 -SR3
O O
II II
-SR9 -SR9
0 0
II II
-sr9 -sr9
II II
O O
-CN -CN
-N, -NOT,
—OSO3R3 —OSO3R3
1-0s02r3 1-0s02r3
-nr3so2r4 -nr3so2r4
—NR3C =NR4 —NR3C = NR4
I I
r3 r3
-nr3c02r4 -nr3c02r4
-no2 -no2
où, relativement aux substituants mentionnés ci-dessus, les groupes R3 et R4 sont choisis indépendamment entre l'hydrogène; les radicaux alkyle, alcényle et alcynyle ayant 1 à 10 atomes de carbone; cycloalkyle, cycloalkylalkyle et alkylcycloalkyle ayant 3 à 6 atomes de carbone dans le noyau cycloalkyle et 1 à 6 atomes de carbone dans les portions alkyliques; phényle; aralkyle, aralcényle et aralcynyle où la portion aryle est un groupe phényle et la portion aliphatique comprend 1 à 6 atomes de carbone; et hétéroaryle, hétéroaralkyle, hétérocyclyle et hétérocyclylalkyle où l'hétéroatome ou les hétéro-atomes des portions hétérocycliques mentionnées ci-dessus sont choisis dans le groupe comprenant 1 à 4 atomes d'oxygène, d'azote ou de soufre et les portions alkyliques associées auxdites portions hétérocycliques comprennent 1 à 6 atomes de carbone, ou bien R3 et R4 peuvent former, conjointement avec l'atome d'azote auquel l'un au moins est lié, un noyau hétérocyclique azoté pentagonal ou hexagonal; R9 a la définition donnée pour R3, à la différence qu'il ne peut pas être de l'hydrogène; ou bien R1 et R8 forment ensemble un groupe alkylidène en C2 à C10 ou alkylidène en C2 à C10 substitué par un radical hydroxy; A est un groupe cyclopentylène, cyclohexy-lène ou alkylène en C2 à C6 éventuellement substitué par un ou plusieurs groupes alkyle en Q à C4; R2 est de l'hydrogène, une charge anionique ou un groupe classique facilement éliminable protégeant la fonction carboxyle, à condition que, lorsque R2 est l'hydrogène ou un groupe protecteur, il y ait également un anion complémentaire, et where, relative to the substituents mentioned above, the groups R3 and R4 are independently chosen from hydrogen; alkyl, alkenyl and alkynyl radicals having 1 to 10 carbon atoms; cycloalkyl, cycloalkylalkyle and alkylcycloalkyle having 3 to 6 carbon atoms in the cycloalkyl ring and 1 to 6 carbon atoms in the alkyl portions; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl portion is a phenyl group and the aliphatic portion comprises 1 to 6 carbon atoms; and heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl where the heteroatom or hetero atoms of the heterocyclic portions mentioned above are selected from the group comprising 1 to 4 atoms of oxygen, nitrogen or sulfur and the alkyl portions associated with said heterocyclic portions comprise 1 to 6 carbon atoms, or else R3 and R4 can form, together with the nitrogen atom to which at least one is linked, a pentagonal or hexagonal nitrogen heterocyclic ring; R9 has the definition given for R3, with the difference that it cannot be hydrogen; or R1 and R8 together form a C2 to C10 alkylidene group or a C2 to C10 alkylidene group substituted by a hydroxy radical; A is a cyclopentylene, cyclohexy-lene or C2-C6 alkylene group optionally substituted by one or more Q-C4 alkyl groups; R2 is hydrogen, an anionic charge or a conventional easily removable group protecting the carboxyl function, provided that, when R2 is hydrogen or a protective group, there is also a complementary anion, and
©/ © /
représente un radical hétérocyclique aromatique monocyclique, bi-cyclique ou polycyclique substitué ou non substitué contenant au moins un atome d'azote dans le noyau et lié à A par l'intermédiaire d'un atome d'azote cyclique de manière à former un groupe ammonium quaternaire. Les réalisations appréciées de ces composés sont décrites en détail dans le brevet de base. Les composés de formule I et leurs sels pharmaceutiquement acceptables sont de puissants agents antibactériens ou des composés intermédiaires utiles à la préparation de ces agents. represents a substituted or unsubstituted monocyclic, bi-cyclic or polycyclic aromatic heterocyclic radical containing at least one nitrogen atom in the nucleus and linked to A via a cyclic nitrogen atom so as to form an ammonium group quaternary. The preferred embodiments of these compounds are described in detail in the basic patent. The compounds of formula I and their pharmaceutically acceptable salts are potent antibacterial agents or intermediate compounds useful in the preparation of these agents.
Les dérivés de carbapenem de formule générale I sont préparés à partir de matières de départ de formule: The carbapenem derivatives of general formula I are prepared from starting materials of formula:
R R
8 ? 8?
O O
dans laquelle R1 et R8 ont les définitions données ci-dessus et R2' représente des groupes classiques aisément éliminables protégeant la fonction carboxyle. Des composés de formule III ont été décrits, par exemple, dans la demande de brevet européen N° 38869 (composé N° 7) et on peut les préparer par les procédés généraux décrits dans cette demande. in which R1 and R8 have the definitions given above and R2 ′ represents easily removable conventional groups protecting the carboxyl function. Compounds of formula III have been described, for example, in European patent application No. 38869 (compound No. 7) and can be prepared by the general methods described in this application.
Un procédé de préparation de composés I, dans lequel les composés de formule II ont la fonction d'un intermédiaire à partir de composants de départ III, peut être résumé par le schéma suivant: A process for the preparation of compounds I, in which the compounds of formula II function as an intermediate from starting components III, can be summarized by the following scheme:
R R
30 30
& 1 & 1
(IH) (IH)
2 ' 2 '
COOR COOR
© ©
élimination facultative delà optional disposal beyond
protection protection
(III) (III)
■COOR ■ COOR
Considérant dans les détails le procédé indiqué ci-dessus, la matière de départ III est amenée à réagir dans un solvant organique inerte tel que le chlorure de méthylène, l'acétonitrile ou le diméthyl-formamide avec une quantité à peu près équimolaire de chlorophos-65 phate de diphényle en présence d'une base telle que la diisopropyl-éthylamine, la triéthylamine, la 4-diméthylaminopyridine ou une base similaire pour obtenir le composé intermédiaire IV. L'acylation en vue de fixer le groupe partant diphénylphosphoryloxy dans la po Considering in detail the process indicated above, the starting material III is reacted in an inert organic solvent such as methylene chloride, acetonitrile or dimethylformamide with an approximately equimolar amount of chlorophos- 65 diphenyl phate in the presence of a base such as diisopropyl-ethylamine, triethylamine, 4-dimethylaminopyridine or a similar base to obtain the intermediate compound IV. Acylation to fix the leaving group diphenylphosphoryloxy in the po
5 5
666272 666272
sition 2 du composé intermédiaire III est avantageusement effectuée à une température d'environ —20 à +40° C, notamment à environ 0° C. Le composé intermédiaire IV peut être isolé éventuellement, mais on l'utilise avantageusement dans l'étape suivante sans isolement ni purification. sition 2 of the intermediate compound III is advantageously carried out at a temperature of approximately —20 to + 40 ° C., in particular at approximately 0 ° C. The intermediate compound IV can optionally be isolated, but it is advantageously used in the following step without isolation or purification.
Le composé intermédiaire IV est ensuite converti en composé intermédiaire V par une réaction classique de déplacement. Ainsi, on peut faire réagir le composé IV avec une quantité à peu près équimo-laire d'un mercaptan de formule: Intermediate compound IV is then converted to intermediate compound V by a conventional displacement reaction. Thus, the compound IV can be reacted with an approximately equimolar amount of a mercaptan of formula:
HS-A-OH HS-A-OH
dans laquelle A représente un groupe cyclopentylène, cyclohexylène ou alkylène en C-2 à C6 éventuellement substitué par un ou plusieurs groupes alkyle en Q à C4 dans un solvant organique inerte tel que le dioxanne, le diméthylformamide, le diméthylsulfoxyde ou l'acéto-nitrile et en présence d'une base telle que la diisopropyléthylamine, la triéthylamine, le bicarbonate de sodium, le carbonate de potassium ou la diméthylaminopyridine. La température de déplacement n'est pas déterminante, mais un intervalle avantageux de températures va d'environ —40 à 25° C. La réaction est conduite le plus avantageusement avec refroidissement, par exemple à environ 0° C. in which A represents a C 2 to C 6 cyclopentylene, cyclohexylene or alkylene group optionally substituted by one or more C to C 4 alkyl groups in an inert organic solvent such as dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile and in the presence of a base such as diisopropylethylamine, triethylamine, sodium bicarbonate, potassium carbonate or dimethylaminopyridine. The displacement temperature is not critical, but an advantageous temperature range is from about -40 to 25 ° C. The reaction is most advantageously carried out with cooling, for example at about 0 ° C.
Le composé intermédiaire V est ensuite acylé avec le chlorure de méthanesulfonyle ou un équivalent acylant fonctionnel de ce composé, tel que l'anhydride d'acide méthanesulfonique, dans un solvant organique inerte et en présence d'une base pour fixer le groupe partant méthanesulfonyloxy du composé intermédiaire VI. L'acylation est conduite dans un solvant organique inerte tel que le tétrahydrofuranne, le chlorure de méthylène, l'acétonitrile ou le diméthylformamide et en présence d'une base convenable telle que la diisopropyléthylamine, la triéthylamine, la 4-diméthylaminopyri-dine, etc. On peut conduire la réaction dans une large plage de températures, par exemple de —40 à +40° C, mais on la conduit très avantageusement en refroidissant, par exemple, à une température d'environ —30 à — 40° C. Intermediate compound V is then acylated with methanesulfonyl chloride or a functional acylating equivalent of this compound, such as methanesulfonic acid anhydride, in an inert organic solvent and in the presence of a base to fix the methanesulfonyloxy leaving group of the intermediate compound VI. The acylation is carried out in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile or dimethylformamide and in the presence of a suitable base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyri-dine, etc. . The reaction can be carried out over a wide temperature range, for example from -40 to + 40 ° C, but it is most advantageously carried out by cooling, for example, to a temperature of about -30 to -40 ° C.
Le composé intermédiaire VI est ensuite soumis à une réaction de déplacement de manière à introduire dans le composé intermédiaire II le groupe iodo partant. Ce groupe particulier s'est montré apte à faciliter grandement la préparation des dérivés de carbapenem de formule I constituant les produits désirés. Les composés intermédiaires nouveaux de formule générale II constituent par conséquent une forme de réalisation appréciée de la présente innovation. The intermediate compound VI is then subjected to a displacement reaction so as to introduce the intermediate iodo group into the intermediate compound II. This particular group has shown itself capable of greatly facilitating the preparation of the carbapenem derivatives of formula I constituting the desired products. The new intermediate compounds of general formula II therefore constitute a preferred embodiment of the present innovation.
Le déplacement du groupe méthanesulfonyloxy partant est effectué par réaction du composé intermédiaire VI avec une source d'ions iodure dans un solvant organique inerte tel que l'acétone, le diméthylformamide ou le diméthylsulfoxyde. On peut utiliser tout composé qui s'ionise dans le solvant utilisé pour produire des ions iodure, par exemple un iodure de métal alcalin tel que Nal ou Kl. La température de déplacement n'est pas déterminante, mais des températures égales ou supérieures à la température ambiante sont très avantageuses pour l'accomplissement de la réaction en une période raisonnable. La source d'ions iodure est utilisée en une quantité choisie de manière qu'il y ait approximativement un équivalent ou un excès d'ion iodure par rapport au composé intermédiaire VI. The displacement of the leaving methanesulfonyloxy group is carried out by reaction of the intermediate compound VI with a source of iodide ions in an inert organic solvent such as acetone, dimethylformamide or dimethylsulfoxide. Any compound which ionizes in the solvent used to produce iodide ions can be used, for example an alkali metal iodide such as Nal or Kl. The displacement temperature is not critical, but temperatures at or above room temperature are very advantageous for carrying out the reaction in a reasonable period of time. The source of iodide ions is used in an amount chosen so that there is approximately an equivalent or excess of iodide ion with respect to intermediate compound VI.
La préparation des dérivés de carbapenem désirés de formule I est effectuée par un déplacement du nucléophile du groupe iodo partant du composé intermédiaire II par le nucléophile hétéroaro-matique azoté désiré: The preparation of the desired carbapenem derivatives of formula I is carried out by a displacement of the nucleophile of the iodo group starting from the intermediate compound II by the desired heteroaramatic nitrogen nucleophile:
n donner des ions argent et un anion inerte, par exemple l'AgC104. En général, on préfère utiliser une quantité approximativement équivalente (par rapport au composé intermédiaire II) d'ion argent pour faciliter le déplacement. On peut conduire la réaction dans une large 5 plage de températures, par exemple d'environ —25 à environ n give silver ions and an inert anion, for example AgC104. In general, it is preferred to use an approximately equivalent amount (relative to intermediate compound II) of silver ion to facilitate movement. The reaction can be carried out over a wide range of temperatures, for example from about -25 to about
+25° C, mais on la conduit le plus avantageusement à une température de l'ordre de 0° C. Le composé intermédiaire T est associé à un anion complémentaire (dérivé du sel d'argent utilisé) qui peut, à ce stade, être substitué par un anion complémentaire différent, par io exemple un anion qui est pharmaceutiquement acceptable, par des procédés classiques. A titre de variante, l'ion complémentaire peut être éliminé ensuite pendant l'opération d'élimination de la protection. + 25 ° C, but it is most advantageously carried out at a temperature of the order of 0 ° C. The intermediate compound T is associated with a complementary anion (derived from the silver salt used) which can, at this stage, be substituted with a different complementary anion, for example an anion which is pharmaceutically acceptable, by conventional methods. Alternatively, the complementary ion can then be removed during the removal of protection process.
15 L'opération d'élimination de la protection, destinée à enlever le groupe R2' protégeant la fonction carboxyle du composé intermédiaire I', est effectuée par des procédés classiques tels que solvolyse, réduction chimique ou hydrogénation. Lorsqu'on utilise un groupe protecteur tel qu'un groupe p-nitrobenzyle, benzyle, benzhydryle ou 20 2-naphtylméthyle qui peut être éliminé par hydrogénation catalytique, le composé intermédiaire I' dans un solvant convenable tel qu'un mélange dioxanne - eau - éthanol, tétrahydrofuranne - mono-hydrogénophosphate dipotassique aqueux - isopropanol ou un solvant similaire peut être traité sous une pression d'hydrogène de 25 0,1 à 0,4 MPa en présence d'un catalyseur d'hydrogénation tel que le palladium fixé sur du charbon, l'hydroxyde de palladium, l'oxyde de platine, etc., à une température de 0 à 50° C, pendant une période d'environ 0,24 à 4 heures. Lorsque R2' est un groupe tel qu'o-nitro-benzyle, la photolyse peut aussi être utilisée pour éliminer la protec-30 tion. Des groupes protecteurs tels que le groupe 2,2,2-trichloréthyle peuvent être éliminés par réduction par le zinc dans des conditions douces. Le groupe allyle protecteur peut être éliminé avec un catalyseur comprenant un mélange d'un composé de palladium et de tri-phénylphosphine dans un solvant aprotique tel que le tétrahydro-35 furanne, l'éther diéthylique ou le chlorure de méthylène. De même, d'autres groupes classiques protégeant la fonction carboxyle peuvent être éliminés par des procédés connus de l'homme de l'art. Enfin, comme mentionné ci-dessus, des composés de formule I' dans laquelle R2' est un ester physiologiquement hydrolysable tel que le 40 groupe acétoxyméthyle, phtalyle, indanyle, pivaloyloxyméthyle, mé-thoxyméthyle, etc., peuvent être administrés directement à l'hôte sans élimination de la protection, attendu que ces esters sont hydro-Iysés in vivo dans des conditions physiologiques. The protective removal operation, intended to remove the group R2 'protecting the carboxyl function of the intermediate compound I', is carried out by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protective group is used such as a p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl group which can be removed by catalytic hydrogenation, the intermediate compound I 'in a suitable solvent such as a dioxane - water - mixture ethanol, tetrahydrofuran - aqueous dipotassium mono-hydrogen phosphate - isopropanol or a similar solvent can be treated under a hydrogen pressure of 0.1 to 0.4 MPa in the presence of a hydrogenation catalyst such as palladium fixed on carbon, palladium hydroxide, platinum oxide, etc., at a temperature of 0 to 50 ° C, for a period of about 0.24 to 4 hours. When R2 'is a group such as o-nitro-benzyl, photolysis can also be used to remove the protection. Protective groups such as the 2,2,2-trichlorethyl group can be removed by reduction with zinc under mild conditions. The protective allyl group can be removed with a catalyst comprising a mixture of a palladium compound and tri-phenylphosphine in an aprotic solvent such as tetrahydro-furan, diethyl ether or methylene chloride. Likewise, other conventional groups protecting the carboxyl function can be eliminated by methods known to those skilled in the art. Finally, as mentioned above, compounds of formula I 'in which R2' is a physiologically hydrolysable ester such as the acetoxymethyl, phtalyl, indanyl, pivaloyloxymethyl, methoxymethyl, etc. group can be administered directly to the host without elimination of protection, since these esters are hydro-lysed in vivo under physiological conditions.
45 45
Exemple 1 : Example 1:
Préparation du 3-(2-iodéthylthio)-6a-[l-(Rj-hydroxyéthyl-7-oxo-I-azabicyclo(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle sch2cb2i co2?nb Preparation of 3- (2-iodethylthio) -6a- [l- (Rj-hydroxyethyl-7-oxo-I-azabicyclo (3.2.0) hept-2-ene-2-carboxylate p-nitrobenzyl sch2cb2i co2? Nb
A. 3-(2-Hydroxyèthylthio)-6a-[l-(R)-hydroxyéthyl]-7-oxo-l-aza-bicyclo(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle A. 3- (2-Hydroxyethylthio) -6a- [l- (R) -hydroxyethyl] -7-oxo-l-aza-bicyclo (3.2.0) p-nitrobenzyl hept-2-ene-2-carboxylate
On fait réagir le composé intermédiaire II avec au moins un équivalent, de préférence un excès, du réactif hétéroarylique désiré dans un solvant organique inerte et en présence d'ion argent. Des solvants organiques inertes convenables comprennent, par exemple, le tètra- 65 hydrofuranne, le dioxanne, le chlorure de méthylène, le diglyme, le diméthoxyéthane, etc. On peut utiliser comme source d'ion argent tout composé d'argent qui s'ionise notablement dans le solvant pour Intermediate compound II is reacted with at least one equivalent, preferably an excess, of the desired heteroaryl reagent in an inert organic solvent and in the presence of silver ion. Suitable inert organic solvents include, for example, tetrahydrofuran, dioxane, methylene chloride, diglyme, dimethoxyethane, etc. Any silver compound which is significantly ionized in the solvent can be used as the silver ion source.
OH OH
r r
'C02?N3 'C02? N3
666 272 666,272
OH OH
,sck2ck2oh , sck2ck2oh
€ €
c02?k3 c02? k3
pKB pKB
■ ■
Une solution de 1,69 g (4,85 mmoles) de 6a-[l-(R)-hydroxy-éthyl]-3,7-dioxo-1 -azabicyclo(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle (1 ) dans 20 ml d'acétonitrile a été refroidie à 0° C sous une atmosphère d'azote. Une solution de 726 mg (7,18 mmoles) de diisopropyléthylamine dans 2 ml d'acétonitrile a été ajoutée, suivie d'une addition goutte à goutte de 1,51 g (5,60 mmoles) de chloro-phosphate de diphényle dans 12 ml d'acétonitrile, en une période de 3 minutes. La solution résultante a été agitée à 0° C pendant 20 minutes pour former le 3-(diphénylphosphoryloxy)-6a-[l-(R)-hydroxy-éthyl]-7-oxo-1 -azabicyclo(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle. On a ajouté à cette solution une solution de 726 mg (7,18 mmoles) de diisopropyléthylamine dans 2 ml d'acétonitrile, puis une solution de 439 mg (5,63 mmoles) de 2-mercaptoéthanol dans 2 ml d'acétonitrile. La solution réactionnelle a été agitée à 0° C pendant 3 heures, puis diluée avec 200 ml d'acétate d'éthyle et lavée avec 200 ml d'eau, 100 ml de H3P04 aqueux à 20% et une solution saturée de sel. L'évaporation de la solution déshydratée (MgS04) a donné une substance semi-solide qui a été triturée avec du chlorure de méthylène et filtrée en donnant 1,2 g (rendement 61%) du produit 2 indiqué dans le titre, sous la forme d'une substance solide amorphe blanche. A solution of 1.69 g (4.85 mmol) of 6a- [l- (R) -hydroxy-ethyl] -3,7-dioxo-1 -azabicyclo (3.2.0) hept-2-ene-2- p-nitrobenzyl carboxylate (1) in 20 ml of acetonitrile was cooled to 0 ° C under a nitrogen atmosphere. A solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml of acetonitrile was added, followed by a dropwise addition of 1.51 g (5.60 mmol) of diphenyl chlorophosphate in 12 ml of acetonitrile, over a period of 3 minutes. The resulting solution was stirred at 0 ° C for 20 minutes to form 3- (diphenylphosphoryloxy) -6a- [1- (R) -hydroxy-ethyl] -7-oxo-1 -azabicyclo (3.2.0) hept- P-nitrobenzyl 2-ene-2-carboxylate. To this solution was added a solution of 726 mg (7.18 mmol) of diisopropylethylamine in 2 ml of acetonitrile, then a solution of 439 mg (5.63 mmol) of 2-mercaptoethanol in 2 ml of acetonitrile. The reaction solution was stirred at 0 ° C for 3 hours, then diluted with 200 ml of ethyl acetate and washed with 200 ml of water, 100 ml of 20% aqueous H3PO4 and a saturated salt solution. Evaporation of the dehydrated solution (MgSO 4) gave a semi-solid substance which was triturated with methylene chloride and filtered giving 1.2 g (yield 61%) of product 2 indicated in the title, in the form of a white amorphous solid.
RMN (DMSO-d6) S: 1,20 (3H, d, J = 6,0 Hz), 2,9-3,2 (9H, m), 5,22 (1H, d, J = 8,5 Hz) et 8,23 (2H, d, J = 8,5 Hz). NMR (DMSO-d6) S: 1.20 (3H, d, J = 6.0 Hz), 2.9-3.2 (9H, m), 5.22 (1H, d, J = 8.5 Hz) and 8.23 (2H, d, J = 8.5 Hz).
IR (KBr) ymax: 3500, 1770 et 1700 cm-'. IR (KBr) ymax: 3500, 1770 and 1700 cm- '.
Analyse pour C]8H20N2O7S: Analysis for C] 8H20N2O7S:
Calculé: C 52,93 H 4,94 N6,86 S 7,85% Calculated: C 52.93 H 4.94 N6.86 S 7.85%
Trouvé: C 52,83 H 4,90 N 6,42 S 8,31% Found: C 52.83 H 4.90 N 6.42 S 8.31%
B. 3-(2-Méthanesulfonyloxyéthylthio)-6a-[l-(R)-hydroxyéthyl]-7- B. 3- (2-Methanesulfonyloxyethylthio) -6a- [1- (R) -hydroxyethyl] -7-
oxo-l-azabicyclo (3.2.0)hept-2-ène-2-carboxylate de p-nitroben- p-nitroben- oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylate
zyle zyle
OH OH
<r <r
.sc-:2ci2o:'i c02?n3 .sc-: 2ci2o: 'i c02? n3
sur MgS04, filtrée et concentrée en un sirop. Cette matière a été purifiée par Chromatographie sur colonne de gel de silice [élution avec un mélange de chlorure de méthylène et d'acétate d'éthyle (3:1 vol./ vol.)] pour obtenir 3,55 g (rendement 75%) du composé indiqué on MgS04, filtered and concentrated in a syrup. This material was purified by column chromatography on silica gel [elution with a mixture of methylene chloride and ethyl acetate (3: 1 vol./vol.)] To obtain 3.55 g (yield 75% ) of the indicated compound
5 dans le titre, sous la forme d'une substance solide amorphe blanche. RMN (CDC13) 8:1,25 (3H, d, J=6,0 Hz), 3,05 (3H, s), 3,06-3,40 (5H, m), 4,05-4,40 (4H, m), 5,25 (1H, d, J= 14,0 Hz), 5,50 (1H, d, J = 14,0 Hz), 7,70 (2H, d, J=8,5 Hz) et 8,23 (2H, d, J=8,5 Hz). IR (KBr) ymax: 3400,1770 et 1600 cm"1. 5 in the title, as a white amorphous solid. NMR (CDC13) 8: 1.25 (3H, d, J = 6.0 Hz), 3.05 (3H, s), 3.06-3.40 (5H, m), 4.05-4, 40 (4H, m), 5.25 (1H, d, J = 14.0 Hz), 5.50 (1H, d, J = 14.0 Hz), 7.70 (2H, d, J = 8 , 5 Hz) and 8.23 (2H, d, J = 8.5 Hz). IR (KBr) ymax: 3400,1770 and 1600 cm "1.
10 Analyse pour CigH^NjOpS^ 10 Analysis for CigH ^ NjOpS ^
Calculé: C 46,90 H 4,56 N4,76% Calculated: C 46.90 H 4.56 N 4.76%
Trouvé: C 46,52 H 4,32 N5,91% Found: C 46.52 H 4.32 N5.91%
15 C. 3-(2-Iodéthylthio)-6a-[l-(R)-hydroxyéthyl]-7-oxo-l-azabicyclo-(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle 15 C. 3- (2-Iodethylthio) -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo- (3.2.0) hept-2-ene-2-carboxylate
OH OH
J- J-
20 20
sch2ch20s02ch3 sch2ch20s02ch3
C02pNB C02pNB
j' i
-sœ2C2X -sœ2C2X
'C02?K; 'C02? K;
30 30
sck2ck20s02ck3 sck2ck20s02ck3
Une solution de 350 mg (0,72 mmole) du composé intermédiaire 3 et de 216 mg (1,4 mmole) d'iodure de sodium dans 20 ml d'acétone a été chauffée au reflux pendant 4 heures. L'évaporation de l'acétone a donné une substance solide amorphe blanche qui a été mise en sus-35 pension dans un mélange de 10 ml d'éther et 10 ml d'eau. Par filtra-tion de la substance solide blanche et séchage sous vide, on a obtenu 300 mg (rendement 80%) du composé 4 indiqué dans le titre, sous la forme d'une poudre amorphe blanche. A solution of 350 mg (0.72 mmol) of intermediate compound 3 and 216 mg (1.4 mmol) of sodium iodide in 20 ml of acetone was heated at reflux for 4 hours. Evaporation of the acetone gave a white amorphous solid which was suspended in a mixture of 10 ml of ether and 10 ml of water. By filtration of the white solid and drying under vacuum, 300 mg (yield 80%) of compound 4 indicated in the title were obtained, in the form of a white amorphous powder.
RMN (DMSO-d6) 5:1,18 (3H, d, J=6,0 Hz), 3,20-3,60 (7H, m), 40 3,80-4,25 (2H, m), 5,10 (1H, d, J=5,5 Hz), 5,25 (1H, d, J=12,0 Hz), 5,45 (1H, d, J= 12,0 Hz), 7,70 (2H, d, J=8,5 Hz) et 8,27 (2H, d, J=8,5 Hz). NMR (DMSO-d6) 5: 1.18 (3H, d, J = 6.0 Hz), 3.20-3.60 (7H, m), 40 3.80-4.25 (2H, m) , 5.10 (1H, d, J = 5.5 Hz), 5.25 (1H, d, J = 12.0 Hz), 5.45 (1H, d, J = 12.0 Hz), 7 , 70 (2H, d, J = 8.5 Hz) and 8.27 (2H, d, J = 8.5 Hz).
IR (KBr) ymax : 3500, 1768 et 1700 cm"1. IR (KBr) ymax: 3500, 1768 and 1700 cm "1.
Analyse pour C18H19N206I: Analysis for C18H19N206I:
Calculé: C 41,71 H 3,70 N5,41 124,48% Calculated: C 41.71 H 3.70 N5.41 124.48%
Trouvé: C 42,10 H 3,75 N 5,97 123,20% Found: C 42.10 H 3.75 N 5.97 123.20%
Exemple 2: Example 2:
50 Préparation du 3-(2-iodopropylthio)-6a-[l-(R)-hydroxyêthyl]-7-oxo-l-azabicyclo (3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle 50 Preparation of 3- (2-iodopropylthio) -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carboxylic acid p-nitrobenzyl
•sc:-.2c:-:2c-:2i • sc: -. 2c: -: 2c-: 2i
'C02?N3 'C02? N3
On a ajouté à -40° C, à une solution de 4,2 g (10,3 mmoles) de composé 2 dans 200 ml de tétrahydrofuranne, 1,3 g (11,3 mmoles) de chlorure de méthanesulfonyle, puis on a ajouté goutte à goutte 1,26 g (12,4 mmoles) de triéthylamine dans 5 ml de tétrahydrofuranne. On a agité le mélange réactionnel pendant 5 heures à —40° C, puis on l'a agité pendant 2 heures à — 30° C sous une atmosphère d'azote et on l'a versé ensuite dans un mélange d'acétate d'éthyle (700 ml) et d'acide phosphorique aqueux à 5% (1000 ml). La phase organique a été lavée avec une solution saturée de sel, déshydratée Was added at -40 ° C to a solution of 4.2 g (10.3 mmol) of compound 2 in 200 ml of tetrahydrofuran, 1.3 g (11.3 mmol) of methanesulfonyl chloride, then 1.26 g (12.4 mmol) of triethylamine in 5 ml of tetrahydrofuran are added dropwise. The reaction mixture was stirred for 5 hours at -40 ° C, then stirred for 2 hours at -30 ° C under a nitrogen atmosphere and then poured into a mixture of acetate ethyl (700 ml) and 5% aqueous phosphoric acid (1000 ml). The organic phase was washed with saturated salt solution, dehydrated
A. 3-(2-Hydroxypropylthio)-6a-[l-(R)-hydroxyéthyl]-7-oxo-l-60 azabicyclo(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle A. 3- (2-Hydroxypropylthio) -6a- [l- (R) -hydroxyethyl] -7-oxo-l-60 azabicyclo (3.2.0) p-nitrobenzyl hept-2-ene-2-carboxylate
O O
11 11
l)(fc}0)2PCl l) (fc} 0) 2PCl
'C02pN3 'C02pN3
2) HSCH2CH2CH2OH 2) HSCH2CH2CH2OH
7 7
666272 666272
oh Oh
A AT
b. 3-(2-Iodopropylthio)-6a-[l-(R)-hydroxyéthyl]-7-oxo-l-azabi-cyclo(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle b. P-nitrobenzyl 3- (2-Iodopropylthio) -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabi-cyclo (3.2.0) hept-2-ene-2-carboxylate
<?- <? -
:h2ck2ch2oh : h2ck2ch2oh
C02pN3 C02pN3
5 TsCl 5 TsCl
Une solution de 926 mg (2,66 moles) de 6-[l-(R)-hydroxyéthyl]- A solution of 926 mg (2.66 moles) of 6- [l- (R) -hydroxyethyl] -
3.7-dioxo-l-azabicyclo(3.2.0)hept-2-ène-2-carboxylate de p-nitrobenzyle (2) dans 15 ml d'acétonitrile a été refroidie à —10° C sous une atmosphère d'azote. Une solution de 349 mg (2,7 mmoles) de diisopropyléthylamine dans 1 ml d'acétonitrile a été ajoutée, suivie d'une addition goutte à goutte de 725 mg (2,0 mmoles) de chloro-phosphate de diphényle dans 0,7 ml d'acétonitrile, en une période de 2 minutes. La solution résultante a été agitée à —10° C pendant 3.7-dioxo-1-azabicyclo (3.2.0) hept-2-ene-2-carboxylate of p-nitrobenzyl (2) in 15 ml of acetonitrile was cooled to -10 ° C under an atmosphere of nitrogen. A solution of 349 mg (2.7 mmol) of diisopropylethylamine in 1 ml of acetonitrile was added, followed by a dropwise addition of 725 mg (2.0 mmol) of diphenyl chlorophosphate in 0.7 ml of acetonitrile, in a period of 2 minutes. The resulting solution was stirred at -10 ° C for
15 minutés en donnant le p-nitrobenzyl-3-(diphénylphosphoryloxy)-6a-[l-(R)-hydroxyéthyl]-7-oxo-l-azabicyclo(3.2.0)hept-2-ène-2-carb-oxylate. On a ajouté à cette solution une solution de 326 mg (2,8 mmoles) de diisopropyléthylamine dans 1 ml d'acétonitrile, puis une solution de 273 mg (3,0 mmoles) de 3-mercaptopropanol dans 0,5 ml d'acétonitrile. Le mélange réactionnel a été agité pendant 5 heures à la température ambiante, puis pendant la nuit à 5° C. Il a été dilué avec 100 ml d'acétate d'éthyle et lavé avec 100 ml d'eau, 15 minutes giving p-nitrobenzyl-3- (diphenylphosphoryloxy) -6a- [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo (3.2.0) hept-2-ene-2-carb-oxylate . To this solution was added a solution of 326 mg (2.8 mmol) of diisopropylethylamine in 1 ml of acetonitrile, then a solution of 273 mg (3.0 mmol) of 3-mercaptopropanol in 0.5 ml of acetonitrile . The reaction mixture was stirred for 5 hours at room temperature, then overnight at 5 ° C. It was diluted with 100 ml of ethyl acetate and washed with 100 ml of water,
puis une solution saturée de sel. Par condensation du solvant déshydraté (MgS04) à un volume d'environ 5 ml, on a obtenu des cristaux blancs qui ont été lavés à l'éther en donnant 830 mg (74%) du produit 3 indiqué dans le titre, sous la forme de cristaux blancs; P. F. 142-144° C. then a saturated salt solution. By condensation of the dehydrated solvent (MgSO 4) to a volume of approximately 5 ml, white crystals were obtained which were washed with ether to give 830 mg (74%) of product 3 indicated in the title, in the form white crystals; M.p. 142-144 ° C.
RMN (DMSO-d6) 8:1,20 (3H, d, J=6,0 Hz), 1,5-2,0 (2H, m), NMR (DMSO-d6) 8: 1.20 (3H, d, J = 6.0 Hz), 1.5-2.0 (2H, m),
2.8-3,6 (7H, m), 4,60 (1H, t, J=5,0 et 5,0 Hz), 5,1 (1H, d, J=5,0 Hz), 5,25 (1H, d, J= 14,0 Hz), 5,50 (1H, d, J= 14,0 Hz), 7,70 (2H, d, J=8,5 Hz) et 8,23 (2H, d, J=8,5 Hz). 2.8-3.6 (7H, m), 4.60 (1H, t, J = 5.0 and 5.0 Hz), 5.1 (1H, d, J = 5.0 Hz), 5.25 (1H, d, J = 14.0 Hz), 5.50 (1H, d, J = 14.0 Hz), 7.70 (2H, d, J = 8.5 Hz) and 8.23 (2H , d, J = 8.5 Hz).
IR (KBr) ymax: 3400,1770 et 1600 cm-1. IR (KBr) ymax: 3400,1770 and 1600 cm-1.
Analyse pour C19H22N2207S- V2H2O : Analysis for C19H22N2207S- V2H2O:
Calculé: C 52,90 H 5,33 N6,49 S 7,42% Calculated: C 52.90 H 5.33 N6.49 S 7.42%
Trouvé: C 53,10 H 5,08 N6,61 S 7,65% Found: C 53.10 H 5.08 N6.61 S 7.65%
25 25
sck'nch.ch.,oso. z 2 2 2 sck'nch.ch., oso. z 2 2 2
02pN3 02pN3
cr," r- C-" I 2 2 2 cr, "r- C-" I 2 2 2
/ ^ / ^
ch. ch.
^02?1® ^ 02? 1®
On a ajouté 400 mg (2,10 mmoles) de chlorure de p-toluènesulfo-nyle à une solution de 810 mg (1,91 mmole) du composé 3 dans 20 ml de tétrahydrofuranne anhydre, puis 268 mg (2,20 mmoles) de diméthylaminopyridine et on agite le mélange pendant 2 heures à la température ambiante sous atmosphère d'azote. Le mélange réactionnel a ensuite été versé dans un mélange d'acétate d'éthyle et d'eau glacée. La phase organique a été lavée avec de l'acide phos-phorique à 40%, puis déshydratée sur MgS04. L'évaporation des solvants déshydratés a donné le tosylate 4 sous la forme d'une huile jaune qui a été convertie en le composé iodé 5, sans aucune autre purification. Le produit brut 4 a été dissous dans 30 ml d'acétone, 1,5 g (10 mmoles) d'iodure de sodium a été ajouté et le mélange a été agité pendant 16 heures à la température ambiante. Le mélange réactionnel a été versé dans un mélange d'acétate d'éthyle et d'eau. 30 L'évaporation du solvant déshydraté (MgS04) a donné un sirop jaune qui a été purifié par Chromatographie sur colonne de gel de silice (élution avec un mélange de chlorure de méthylène et d'acétate d'éthyle à 9:1 vol./vol.) et on a obtenu 142 mg (rendement 18,5%) du composé indiqué dans le titre sous la forme d'une poudre 35 amorphe blanche. 400 mg (2.10 mmol) of p-toluenesulfonyl chloride was added to a solution of 810 mg (1.91 mmol) of compound 3 in 20 ml of anhydrous tetrahydrofuran, then 268 mg (2.20 mmol) of dimethylaminopyridine and the mixture is stirred for 2 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then poured into a mixture of ethyl acetate and ice water. The organic phase was washed with 40% phos-phoric acid, then dried over MgSO4. Evaporation of the dehydrated solvents gave the tosylate 4 as a yellow oil which was converted to the iodized compound 5 without any further purification. The crude product 4 was dissolved in 30 ml of acetone, 1.5 g (10 mmol) of sodium iodide was added and the mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water. Evaporation of the dehydrated solvent (MgSO4) gave a yellow syrup which was purified by column chromatography on silica gel (elution with a mixture of methylene chloride and ethyl acetate at 9: 1 vol./ vol.) and 142 mg (18.5% yield) of the title compound was obtained as a white amorphous powder.
RMN (acétone-d,;): 1,25 (3H, d, J=6,0 Hz), 2,7-3,5 (7H, m), 4,0-4,4 (2H, m), 5,30 (1H, d, J= 14,0 Hz), 5,65 (1H, d, J= 14,0 Hz), 7,80 (2H, d, J=8,5 Hz), 8,30 (2H, d, J=8,5 Hz). NMR (acetone-d,;): 1.25 (3H, d, J = 6.0 Hz), 2.7-3.5 (7H, m), 4.0-4.4 (2H, m) , 5.30 (1H, d, J = 14.0 Hz), 5.65 (1H, d, J = 14.0 Hz), 7.80 (2H, d, J = 8.5 Hz), 8 , 30 (2H, d, J = 8.5 Hz).
IR (KBr) max: 3500,1770 et 1600 cm"1. IR (KBr) max: 3500,1770 and 1600 cm "1.
R R
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36691082A | 1982-04-09 | 1982-04-09 | |
| US06/471,379 US4552696A (en) | 1982-04-09 | 1983-03-08 | Carbapenem antibiotics |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH666272A5 true CH666272A5 (en) | 1988-07-15 |
Family
ID=27003573
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH2956/86A CH666272A5 (en) | 1982-04-09 | 1983-04-08 | CARBAPENEM DERIVATIVES. |
| CH1916/83A CH657854A5 (en) | 1982-04-09 | 1983-04-08 | CARBAPENEM DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, COMPOUNDS FOR THEIR PREPARATION, AND METHODS OF PRODUCING THE SAME. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1916/83A CH657854A5 (en) | 1982-04-09 | 1983-04-08 | CARBAPENEM DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, COMPOUNDS FOR THEIR PREPARATION, AND METHODS OF PRODUCING THE SAME. |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4552696A (en) |
| KR (1) | KR880001069B1 (en) |
| AT (1) | AT382620B (en) |
| AU (1) | AU572090B2 (en) |
| BE (1) | BE896418A (en) |
| CA (2) | CA1283659C (en) |
| CH (2) | CH666272A5 (en) |
| DE (1) | DE3312533A1 (en) |
| DK (1) | DK157083A (en) |
| ES (2) | ES521293A0 (en) |
| FI (1) | FI76801C (en) |
| FR (1) | FR2524890B1 (en) |
| GB (2) | GB2119371B (en) |
| GR (1) | GR78185B (en) |
| HU (1) | HU190083B (en) |
| IE (1) | IE54769B1 (en) |
| IL (1) | IL68148A0 (en) |
| IT (1) | IT1200926B (en) |
| LU (1) | LU84740A1 (en) |
| NL (1) | NL8301212A (en) |
| OA (1) | OA07390A (en) |
| PT (1) | PT76525B (en) |
| SE (2) | SE460790B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1198440A (en) * | 1982-04-08 | 1985-12-24 | Choung U. Kim | Carbapenem antibiotics |
| US4642341A (en) * | 1982-04-09 | 1987-02-10 | Bristol-Myers Company | Carbapenem antibiotics |
| US4536335A (en) * | 1982-06-18 | 1985-08-20 | Bristol-Myers Company | Carbapenem antibiotics |
| DK140584A (en) * | 1983-03-08 | 1984-09-09 | Bristol Myers Co | PROCEDURE FOR THE PREPARATION OF CARBAPENE DERIVATIVES |
| CA1285940C (en) * | 1984-07-02 | 1991-07-09 | Merck & Co., Inc. | Carbapenems having a 2-quaternary heteroarylalkylthio substituent |
| IE851586L (en) * | 1984-07-02 | 1986-01-02 | Interchem Internat S A | I methylcarbapenems having a 2-quaternary¹heteroarylalkylthio substituent |
| US4729993A (en) * | 1984-12-13 | 1988-03-08 | Merck & Co., Inc. | Carbapenems and 1-methylcarbapenems having an externally alkylated mono- or bicyclic 2-quaternary heteroarylalkyl substituent |
| US4680292A (en) * | 1984-12-13 | 1987-07-14 | Merck & Co., Inc. | Carbapenems and 1-methylcarbapenems having a 2-heteroaryliumaliphatic substituent |
| US4725594A (en) * | 1984-12-13 | 1988-02-16 | Merck & Co., Inc. | Carbapenems having an internally or externally alkylated mono- or bicyclic 2-quaternary heteroarylalxyl heteromethyl substituent |
| US4952397A (en) * | 1985-06-17 | 1990-08-28 | Merck & Co., Inc. | 2-quaternary heteroarylalkylthio carbapenems having an acid moiety substituent |
| US4665169A (en) * | 1985-09-11 | 1987-05-12 | Bristol-Myers Company | Carbapenem antibiotics |
| US4880922A (en) * | 1985-11-22 | 1989-11-14 | Bristol-Myers Company | Carbapenems with quaternized heterothioalkylthio substitution at position 2 |
| US4894450A (en) * | 1987-05-11 | 1990-01-16 | Merck & Co., Inc. | Process for 2-(aminoalkylthio) carbapenems |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4235920A (en) * | 1975-11-21 | 1980-11-25 | Merck & Co., Inc. | N-Alkylated derivatives of thienamycin |
| NL7612937A (en) * | 1975-11-21 | 1977-05-24 | Merck & Co Inc | THIENAMYCINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS AND THE PROCESS FOR PREPARING THEM. |
| US4235917A (en) * | 1977-05-05 | 1980-11-25 | Merck & Co., Inc. | N-Alkyl-N-acyl derivatives of thienamycin |
| US4189493A (en) * | 1977-12-28 | 1980-02-19 | Merck & Co., Inc. | N-heterocyclic derivatives of thienamycin |
| AR228726A1 (en) * | 1978-05-26 | 1983-04-15 | Glaxo Group Ltd | PROCEDURE FOR THE PREPARATION OF ANTIBIOTIC (6R, 7R) -7 - ((Z) -2- (2-AMINOTIAZOL-4-IL) -2- (2-CARBOXIPROP-2-OXIIMINO) ACETAMIDO) -3- (1- PIRIDINIOMETIL) CEF-3-EM-4-CARBOXILATO |
| JPS5625110A (en) * | 1978-12-18 | 1981-03-10 | Bristol Myers Co | Antibacterial |
| EP0082133A3 (en) * | 1979-04-19 | 1983-07-20 | Merck & Co. Inc. | A process for preparing intermediates useful for preparing 2-substituted-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids |
| US4376774A (en) * | 1979-05-29 | 1983-03-15 | Merck & Co., Inc. | Antibiotic N-heterocyclyl thienamycin |
| DE3169321D1 (en) * | 1980-03-27 | 1985-04-25 | Merck & Co Inc | Process for the preparation of 1-carbapenems and intermediates via silyl-substituted dithioacetals |
| EP0038869A1 (en) * | 1980-04-30 | 1981-11-04 | Merck & Co. Inc. | Process for the preparation of 1-carbapenems, and intermediates for their preparation |
| EP0044170A1 (en) * | 1980-07-11 | 1982-01-20 | Beecham Group Plc | Beta-lactam antibiotics, their preparation and use |
| WO1983000867A1 (en) * | 1981-09-09 | 1983-03-17 | Takeda Chemical Industries Ltd | 5,6-cis-carbapenem-3-carboxylic acid derivatives and process for their preparation |
| EP0074599A1 (en) * | 1981-09-09 | 1983-03-23 | Takeda Chemical Industries, Ltd. | 5,6-cis-Carbapenem derivatives, their production and use |
| WO1983002614A1 (en) * | 1982-02-02 | 1983-08-04 | Takeda Chemical Industries Ltd | 5,6-cis-carbapenem-3-carboxylic acid derivatives and process for their preparation |
| CA1198440A (en) * | 1982-04-08 | 1985-12-24 | Choung U. Kim | Carbapenem antibiotics |
| US4536335A (en) * | 1982-06-18 | 1985-08-20 | Bristol-Myers Company | Carbapenem antibiotics |
| DK140584A (en) * | 1983-03-08 | 1984-09-09 | Bristol Myers Co | PROCEDURE FOR THE PREPARATION OF CARBAPENE DERIVATIVES |
-
1983
- 1983-03-08 US US06/471,379 patent/US4552696A/en not_active Expired - Fee Related
- 1983-03-16 IL IL68148A patent/IL68148A0/en not_active IP Right Cessation
- 1983-03-23 AU AU12726/83A patent/AU572090B2/en not_active Ceased
- 1983-03-31 CA CA000425064A patent/CA1283659C/en not_active Expired - Fee Related
- 1983-04-05 OA OA57961A patent/OA07390A/en unknown
- 1983-04-05 FR FR8305521A patent/FR2524890B1/en not_active Expired
- 1983-04-06 FI FI831170A patent/FI76801C/en not_active IP Right Cessation
- 1983-04-06 NL NL8301212A patent/NL8301212A/en not_active Application Discontinuation
- 1983-04-07 ES ES521293A patent/ES521293A0/en active Granted
- 1983-04-07 SE SE8301929A patent/SE460790B/en not_active IP Right Cessation
- 1983-04-07 DE DE19833312533 patent/DE3312533A1/en active Granted
- 1983-04-07 GR GR71027A patent/GR78185B/el unknown
- 1983-04-08 BE BE0/210521A patent/BE896418A/en not_active IP Right Cessation
- 1983-04-08 LU LU84740A patent/LU84740A1/en unknown
- 1983-04-08 HU HU831225A patent/HU190083B/en not_active IP Right Cessation
- 1983-04-08 PT PT76525A patent/PT76525B/en not_active IP Right Cessation
- 1983-04-08 DK DK157083A patent/DK157083A/en not_active IP Right Cessation
- 1983-04-08 IT IT48068/83A patent/IT1200926B/en active
- 1983-04-08 CH CH2956/86A patent/CH666272A5/en not_active IP Right Cessation
- 1983-04-08 IE IE806/83A patent/IE54769B1/en not_active IP Right Cessation
- 1983-04-08 AT AT0125683A patent/AT382620B/en not_active IP Right Cessation
- 1983-04-08 GB GB08309566A patent/GB2119371B/en not_active Expired
- 1983-04-08 CH CH1916/83A patent/CH657854A5/en not_active IP Right Cessation
- 1983-04-09 KR KR1019830001529A patent/KR880001069B1/en not_active IP Right Cessation
- 1983-12-15 ES ES528079A patent/ES8601118A1/en not_active Expired
-
1985
- 1985-06-14 GB GB08515162A patent/GB2159818B/en not_active Expired
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1986
- 1986-03-20 CA CA000504685A patent/CA1284500C/en not_active Expired - Fee Related
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1989
- 1989-03-22 SE SE8901032A patent/SE8901032D0/en not_active Application Discontinuation
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